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Liposomes with selective and controllable surface reactivity : applications for tumor specific thrombosis

University of British Columbia

The possibility to selectively induce thrombosis in tumor blood vessels offers an interesting approach to attack solid tumors. With the well known propensity of phosphatidylserine (PS) containing membranes to bind blood coagulation proteins with high affinity and catalyze coagulation reactions, it is hypothesized that a tumor vasculaturetargeted liposome containing PS may provide a means to achieve a therapeutic response based on this principle. This thesis presents a stepwise approach to the design of such liposomes. In order to develop thrombogenic liposomes that are able to induce tumor specific blood coagulation while avoiding unwanted side effects, several features must be engineered into the formulation. First, the PS liposome surface should be protected in circulation to prevent unwanted blood coagulation reactions and rapid plasma removal of such liposomes. Results from Chapters 2 and 3 have demonstrated that an elevated level (15 mol%) of poly(ethylene glycol)-conjugated lipids (PEG-lipids) is required to prevent the PS-mediated binding of blood coagulation proteins and the rapid removal of PS liposomes. While adequate protection of the PS liposome surface is essential in the circulation, exposure of the thrombogenic PS liposome surface is necessary to trigger the blood coagulation reactions once the liposomes have reached tumor blood vessels. Results from Chapter 4 demonstrate the potential of combining PEG-lipids which have different rates of desorption from PS liposomes to balance PS surface exposure and protection. In addition to controlling the surface thrombogenicity of the PS liposomes, localizing the blood coagulation response within the tumor blood vessels is desirable. A monoclonal antibody (Ab) that recognizes a surface marker selectively expressed on the tumor vascular endothelium was conjugated to the PS liposomes in an attempt to demonstrate localization of the coagulation response. The in vitro results from Chapter 5 demonstrate the potential of PS liposomes targeted to activated endothelial cells to selectively trigger thrombogenesis. Although specific delivery of the Ab-conjugated PS liposomes to tumor vasculature was not demonstrated in LSI 80 tumor bearing mice, attributes important to the in vivo targeting of such liposomes are discussed. The results from these studies provide the basis for developing thrombogenic liposomes that can be selectively activated in tumor vasculature to achieve therapeutic response.

Thesis/Dissertation

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2009-11-13

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http://hdl.handle.net/2429/14914

Pharmaceutical Sciences

University of British Columbia

UBCV

DSpace